This proposal is a competitive renewal of R01 DK64832 previously titled "Neurocognitive effects of hypoglycemia in T1DM". That grant hypothesized that prior severe hypoglycemia would reduce memory and hippocampal volume in youth with type 1 diabetes mellitus (T1DM). In the process of addressing this relatively narrow question, we have collected a uniquely large developmental neuroimaging and cognitive dataset in youth with T1DM that now allows us to examine broader and more complex issues. In light of new data and hypotheses, we have renamed the grant "Glycemic control, brain structure and cognitive development in T1DM". We now are able to address whether there is a differential effect of severe hypoglycemia (Hypo) and chronic hyperglycemia (Hyper) on the developmental trajectories of brain regions and whether these structural effects are reflected in changes in cognitive function. In our analyses to date, we found that a retrospective history of severe Hypo in youth with T1DM was associated with reduced volume in the posterior temporal- parietal cortex and reduced memory skills. In contrast, a retrospective history of Hyper in these same youth was associated with reduced volume in medial occipital-parietal cortex and lower verbal intelligence. These results are consistent with growing evidence that exposure to glycemic extremes has permanent consequences for the structural and functional integrity of these cortical regions. However, these data have come from retrospective studies and so the direction of causality can only be hypothesized. To address this ambiguity, prospective data are greatly needed. Our prior grant enrolled and characterized a large sample of youth with T1DM and followed them for two years. We now have new preliminary prospective data that demonstrate altered developmental trajectories of gray and white matter in the brain related to Hyper exposure during a 2 year follow-up period. However, the low frequency of severe Hypo during this time did not allow us to test hypotheses about Hypo's effects on brain development. To capture a wider range of exposure and enhance our power to test hypotheses we propose to follow this uniquely characterized cohort for 3 more years to assess change in brain structure and cognitive function over a full 5 years of T1DM. In addition, on the basis of new preliminary data suggesting that exposure to Hyper affects white matter microstructural integrity (measured with diffusion tensor imaging or DTI) in addition to regional brain volume, we propose to add state- of-the-art DTI measures to complement our existing measures. Finally, in order to more conclusively determine whether there are any differences at baseline in T1DM, we will add a newly diagnosed cohort to our longitudinal study. This plan, combined with our neuroimaging expertise and well-characterized existing cohort, places us in a unique position to test strong hypotheses about how glycemic extremes, brain structural integrity and cognitive function are related in youth with T1DM. PUBLIC HEALTH RELEVANCE: The goal of this project is to help determine whether central nervous system structure and function should join the peripheral nervous system, retina and kidneys as systems at risk during development in T1DM. This knowledge would have significant clinical implications for the optimal care of youth with T1DM.